Elemental iodine (I2) is a blue-black crystal with a high metallic luster that sublimes readily to generate a violet-colored vapor. In solution, the term “molecular iodine” has been used to refer to the I2 molecule. Molecular iodine (I2) is a hydrophobic molecule that is highly polarizable. The chemical reactivity of I2 includes: addition to double bonds, oxidization of sulphydral groups, addition to activated aromatic groups and formation of N-iodo derivatives. However, iodine also reacts with water to form iodine species that exist in several different oxidation states; molecular iodine is unstable in water due to these reactions.
The term “iodine” has been, and continues to be used imprecisely in medical literature to refer to several different chemical entities and complicated formulations that contain diverse iodine species. The imprecise description of iodine compositions in the art may stem, in part, from ambiguous analytical characterizations. For example, thiosulfate titration is the most commonly used USP method to measure I2 but this method also detects triiodide and hypoiodous acid in addition to molecular iodine (I2). From this point forward the present application shall use the term “molecular iodine” (I2) or “uncomplexed molecular iodine” when referring to the I2 species in an aqueous environment.
In an aqueous environment iodine exists in several forms or species. These species include: iodide (I−), molecular iodine (I2), hypoiodous acid (HOI), iodate (IO3−), triiodide (I3−) and polyiodides (e.g., I5− or I7−). These species have different physical and chemical properties. The instability of polyvinylpyrrolidone-iodine (PVP-I) or starch-iodine compositions is primarily caused by hydration of molecular iodine to form hypoiodous acid which ultimately leads to formation of iodate and loss of iodine atoms from the complex equilibrium that yields a very low concentration of uncomplexed molecular iodine. Uncomplexed molecular iodine is responsible for the biocidal activity of iodine germicides. The instability of molecular iodine in an aqueous environment is a primary formulation constraint that has influenced the development of all aqueous based iodine germicides that rely upon complexed molecular iodine.
Four basic formulation strategies have been used to overcome aqueous I2 instability. These include: (a) the use of iodide as a complexing agent, (b) the use of organic complexing agents such as polyvinylpyrrolidone, starch and other complexing agents which complex I2, (c) solid compositions that release elemental iodine slowly and (d) the use of oxidation reactions to produce iodine in situ. Each approach has inherent constraints and potential benefits that need to be evaluated in light of an intended application. However, adopting a formulation strategy that requires complexation of molecular iodine i.e., the two strategies identified as (a) and (b) above, necessarily require incorporation of considerably more iodine than an approach based on uncomplexed iodine in order to provide a similar biocidal capability.
Formulations based on iodine-complexation require additives that reduce the chemical activity of molecular iodine in a composition via the expedient of a relatively tight binding between said additive and molecular iodine. That is, the binding between complexing agent and molecular iodine must be tight enough to prevent hydration of molecular iodine. This approach results in a very low concentration of free or uncomplexed molecular iodine and a very high concentration of bound molecular iodine. As an example, commonly used 10% PVP-I typically delivers 2-4 ppm of unbound molecular iodine in a composition that contains over 15,000 ppm of total iodine atoms. The level of total iodine is obviously much higher than that amount of pure molecular iodine required for biocidal efficacy. Drawbacks of such compositions include undesirable toxicological properties, unwanted interactions with inanimate materials, increased costs and a higher environmental burden, as well as limited efficacy for many indications due to low concentrations of uncomplexed iodine and poor stability upon dilution.
U.S. Pat. No. 5,629,024 describes methods to generate molecular iodine in an aqueous environment, but the compositions described therein do not have a useful activated use-life because the molecular iodine is dissipated rapidly via reaction with water. Despite the fact that the compositions described in U.S. Pat. No. 5,629,024 patent do not require high levels of molecular iodine the patent does require generation of molecular iodine by the peroxysulfate anion at a controlled rate equal to the rate of loss of molecular iodine. Although this approach is viable, the method described in U.S. Pat. No. 5,629,024 is limited to applications where the loss of molecular iodine is equivalent to, or slightly greater than, the minimum generation rate of molecular iodine over the intended period of use. Additionally, the method described in U.S. Pat. No. 5,629,024 requires users to activate the composition of interest prior to use since it cannot provide a stable formulation that can be manufactured and placed into commercial distribution channels, resulting in unnecessary inconvenience and chance of operator error.
The use of iodate in iodophor compositions is a well-known formulation approach to one skilled in the art that is used to increase the stability of molecular iodine in these complex formulations. Winicov and Oberlander (U.S. Pat. No. 4,271,149) described methods to stabilize complexed iodine compositions via the use of an iodate ion in the range of about 0.005% to 0.2% within a pH range of pH 5-7. McKinzie and Winicov (U.S. Pat. No. 5,643,608) developed iodophors with high levels of molecular iodine using mixtures of iodine-iodide-iodate compositions with stability for 1 to 3 months which contained 0.005-0.5% iodate by weight in a pH range of about 2.0-4.5. Buxton et. al. (EP0448288 B1) describes the use of iodate in a concentration range of 0.01% to 0.04% in stabilized iodophors to provide reduced irritancy. Khan and Moellmer (U.S. Pat. No. 5,116,623) describe the use of periodate to stabilize iodophors. All of these patents described iodine formulations wherein the iodine is complexed and therefore the interaction of iodate in these iodide rich environments is not precisely controlled or predictable in contrast to the present invention.
The marketplace has shown a long-felt need for a storage stable, non-toxic germicide that can reduce transmission of infectious agents and inactivate resistant microbial strains. For example, microbial infections, from viruses, spores, bacteria, fungi, etc., for example, Norovirus infections, which induce stomach pain, nausea, diarrhea and vomiting, place a significant economic and health burden on society. Norovirus and other viruses and bacteria are transmitted by human contact, contaminated food or water, or by touching contaminated surfaces. Proper prevention techniques in the healthcare and food preparation workplace require repeated daily hand disinfection which can be problematic since efficacious hand sanitizers often cause irritation when used chronically. The same problem persists in hospitals with respect to the cause of nosocomial infections and resistant staphylococcus (MRSA) and streptococcus infections, among numerous others. A key objective of the formulations contemplated in this application is the rapid elimination (in some cases to unmeasurable numbers) of viruses, spores, bacteria and fungi such as norovirus and all resistant bacterial microbes, especially including, for example, multiple drug resistant staph infections (MRSA).
The annual economic cost of food spoilage to producers, processors, transporters, retailers and consumers is estimated to be $750 billion dollars globally. Approximately 1.3 billion tons of foods are wasted every year. This spoilage is primarily caused by the action of microbes on the surfaces of the affected foodstuffs (meats, berries, vegetables, fruits, seafood and grains). The compositions described in this application are suitable to both sanitize and extend the shelf life of many foods thereby providing a significant economic benefit.